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A male patient underwent gastrojejunal bypass surgery in 2017. In 2020, he was referred to our hospital for suspected obstructive jaundice. Subsequently, he was diagnosed with cholangiocarcinoma, and endoscopic retrograde cholangiopancreatography was attempted via balloon-assisted enteroscopy. However, the endoscope did not reach the duodenal papilla owing to the abdomen-small intestine adhesion. Therefore, endoscopic ultrasound-guided hepaticogastrostomy was performed using a dedicated plastic stent. After stent placement, obstructive jaundice and cholangitis promptly improved. However, we replaced the plastic stent with a fully covered self-expandable metal stent because stent occlusions occurred frequently. Two months after fully covered self-expandable metal stent placement, the patient developed cholangitis again. Notably, during the endoscopic procedure, the stent was found to be completely migrated. Nevertheless, the fistula was still open, and the patient was successfully retreated with the maintained fistula of endoscopic ultrasound-guided hepaticogastrostomy., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Background and Objectives: Currently, there are no reports on the learning curve of endoscopic ultrasound-guided hepaticogastrostomy (EUS-HGS) using dedicated plastic stents. Therefore, we evaluated the outcomes of EUS-HGS using dedicated plastic stents at tertiary referral centers during the initial development phase of EUS-HGS., Materials and Methods: Endoscopic retrograde cholangiopancreatography (ERCP) was strictly prioritized over EUS-HGS. Twenty-three consecutive patients treated using EUS-HGS with a 7-Fr dedicated plastic stent over 4 years beginning in 2018 were analyzed retrospectively., Results: The most common primary disease was pancreatic cancer, and the most common reason for difficulty in ERCP was duodenal obstruction, followed by surgically altered anatomy. The overall technical success rate of EUS-HGS was 95.7% (22/23). One failed case was converted to EUS-guided choledochoduodenostomy. The clinical success rate was 90.9% (20/22). Adverse events (AEs) related to the procedure were observed in four (17.4%) patients, including mild biliary peritonitis in three (13.0%) and mild cholangitis in one (4.3%) patient; all patients received conservative therapy. No serious AEs, such as stent migration, bleeding, or gastrointestinal perforation, were observed. Recurrent biliary obstruction (RBO) was observed in eight (34.8%) patients. Of these, HGS stent replacement was performed in four patients, and other treatments were performed in the remaining four patients. Another four (17.4%) patients did not develop RBO but underwent periodic HGS stent replacement., Conclusions: EUS-HGS using a dedicated plastic stent was performed safely even in its initial phase of introduction. The approach using this stent can be useful in case of ERCP failure for biliary decompression because of the high feasibility and low risk of serious adverse events.

Objectives: Serial pancreatic juice aspiration cytological examination (SPACE) via endoscopic retrograde cholangiopancreatography is a useful diagnostic method for early-stage pancreatic cancer, such as carcinoma in situ that are difficult to diagnose by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). However, the diagnostic accuracy of SPACE is low, which is attributed to problems regarding specimen treatment. Hence, we evaluated the diagnostic efficacy of liquid-based cytology (LBC) in pancreatic juice cytology for pancreatic cancer., Methods: We retrospectively analyzed 24 patients with suspected pancreatic cancer that was difficult to diagnose by endoscopic ultrasound-guided fine needle aspiration who underwent SPACE using LBC between April 2017 and April 2021., Results: The most common reason for performing SPACE was localized stenosis of the main pancreatic duct without a mass. Eleven patients were diagnosed with malignancy after surgical resection, nine of whom had pancreatic ductal adenocarcinoma. Ten patients were diagnosed as benign after a follow-up of more than 1 year. The nine cases of malignancy were diagnosed before surgical resection by SPACE using LBC, with a sensitivity of 81.8% and specificity of 100%. The overall diagnostic accuracy was 91.7%. A total of 152 LBC examinations were performed via SPACE, with an adequate sample collection rate of 88.9%. No adverse events, including acute pancreatitis, occurred after endoscopic retrograde cholangiopancreatography., Conclusion: SPACE with LBC offers good diagnostic efficacy in patients with pancreatic cancer that is difficult to diagnose by endoscopic ultrasound-guided fine needle aspiration., Competing Interests: The authors declare that they have no conflict of interest., (© 2022 The Authors. DEN Open published by John Wiley & Sons Australia, Ltd on behalf of Japan Gastroenterological Endoscopy Society.)

The prognosis of highly advanced unresectable hepatocellular carcinoma (HCC) with a portal vein tumor thrombus (PVTT) is poor. There are currently no reports of long-term survival for up to 5 years in patients with advanced HCC who were treated with sorafenib. We describe a patient with Vp4 HCC who was treated with a sorafenib-based multidisciplinary treatment and experienced long-term survival, which may be the longest survival to date. A man in his late 60 s presented with general fatigue. Eight years previously, he received interferon monotherapy for chronic hepatitis C for 48 weeks and achieved a sustained virological response. He was diagnosed with a PVTT (Vp4) with diffuse-type HCC in the S6 lobe of the liver. He received hepatic arterial infusion of chemotherapy using 5-fluorouracil and cisplatin. Because of the occurrence of adverse effects, he was placed on sorafenib treatment. The treatment was effective and the HCC reduced. However, after 3 years of treatment, a 2-cm HCC was observed in the S5 lobe, and the patient underwent laparoscopic partial hepatectomy. After the operation, he continued to receive sorafenib, with no obvious recurrence, and survived for over 108 months after the first treatment. There are currently no reported cases of long-term progression-free survival by sorafenib for five years in patients of Vp4 HCC. In conclusion, we report a case of longest survival of a patient with Vp4 HCC treated with sorafenib-based multidisciplinary treatment., (© 2022. Japanese Society of Gastroenterology.)

Background/aims: Covered self-expandable metallic stents (CMSs) are widely used for malignant distal biliary obstructions (MDBOs) caused by pancreatic carcinoma. This study compared the efficacy and safety of the laser-cut-type and braided-type CMSs., Methods: To palliate MDBOs caused by pancreatic carcinoma, the laser-cut-type CMSs was used from April 2014 to March 2017, and the braided-type CMSs was used from April 2017 to March 2019. The tested self-expandable metallic stents were equipped with different anti-migration systems., Results: In total, 47 patients received CMSs for MDBOs (24 laser-cut type, 23 braided-type). The time to recurrent biliary obstruction (TRBO) was significantly longer in the braided-type CMSs (p=0.0008), and the median time to stent dysfunction or patient death was 141 and 265 days in the laser-cut-type CMSs and braided-type CMSs, respectively (p=0.0023). Stent migration was the major cause of stent dysfunction in both groups, which occurred in 37.5% of the laser-cut-type CMSs and 13.0% of the braidedtype CMSs. There were no differences in the survival duration between the groups., Conclusion: The TRBO was significantly longer for the braided-type CMSs with an anti-migration system than for the laser-cuttype. Stent migration tended to be less frequent with the braided-type CMSs than with the laser-cut-type CMSs.

Objective: Nonalcoholic steatohepatitis (NASH) is difficult to diagnose in patients with no symptoms. We aimed to investigate the combined effect of farnesoid X receptor (FXR) agonist, obeticholic acid (OCA), and angiotensin II type 1 receptor blocker (ARB: losartan) on an ongoing hepatic fibrosis in a NASH rat model., Methods: Fischer 344 rats were fed with choline-deficient L-amino-acid-defined (CDAA) diet for 16 weeks. After 8-week administration of CDAA diet, OCA, losartan, or a combination of these drugs was administered at a dose of 30 mg/kg/day for 8 weeks by oral gavage. The in vivo and in vitro effects of OCA + losartan and liver fibrosis progression, lipopolysaccharide (LPS), Toll-like receptor 4 (TLR4) regulatory cascade, and gut barrier function were evaluated., Results: OCA + losartan alleviated hepatic fibrosis progression by suppressing α-SMA expression. It inhibited the proliferation of activated hepatic stellate cell (Ac-HSC) and mRNA expression of hepatic transforming growth factor-β1 (TGF-β1), TLR4, and tissue inhibitor of metalloproteinase-1 (TIMP-1) and decreased the hydroxyproline levels. OCA increased the hepatic matrix metalloproteinase-2 (MMP-2) mRNA expression. OCA decreased the mRNA expression of hepatic LPS-binding protein and intestinal permeability by ameliorating the disruption of CDAA diet-induced zonula occludens-1. Losartan directly inhibited the proliferation of Ac-HSC. The in vitro suppressive effects of OCA + losartan on the mRNA expressions of TGF-β1 and α1(I)-procollagen, TLR4, and TIMP-1 in Ac-HSCs were almost in parallel., Conclusions: OCA + losartan suppressed the ongoing hepatic fibrosis by attenuating gut barrier dysfunction and suppressing Ac-HSC proliferation. Combined therapy may be a promising novel approach for NASH with fibrosis., (© 2021. Indian Society of Gastroenterology.)

Background/aim: Sarcopenia increases the mortality in patients with cirrhosis. Approximately 60% of zinc is accumulated in skeletal muscle. We aimed to determine the role of subclinical zinc deficiency on sarcopenia development in patients with cirrhosis., Patients and Methods: We enrolled 151 patients with cirrhosis and divided them into the group with normal serum zinc levels (Group N: 80-130 μg/dl; n=38) and group with subclinical zinc deficiency (Group D: <80 μg/dl; n=113). The risk factors for sarcopenia were then investigated., Results: Group D had more sarcopenia cases than Group N (31.0% vs. 13.2%). In group D, HGS exhibited a weakly positive but significant correlation with serum zinc levels (R=0.287, p=0.00212), serum zinc levels negatively correlated with both ammonia and myostatin levels (R=-0.254, p=0.0078; R=-0.33, p<0.01), and low zinc levels were independently associated with sarcopenia development., Conclusion: Patients with cirrhosis showing subclinical zinc deficiency have a significantly higher risk of developing sarcopenia., Competing Interests: The Authors declare no conflicts of interest., (Copyright 2022, International Institute of Anticancer Research.)

Equol is a metabolite of daidzein, a major soybean isoflavone with estrogenic and antioxidant activities. As the production of equol depends on the presence of certain members of the intestinal microflora, not all individuals can produce equol. We examined the relationship between NASH histological features and equol production. In an animal model, obese OLETF rats were intraperitoneally injected with a porcine serum to augment liver fibrogenesis. Equol-rich soy product, SE5-OH was orally administered during the experimental period. Treatment with SE5-OH markedly attenuated the development of liver fibrosis and expression of alpha-smooth muscle actin. In clinical research, 38 NAFLD patients (13 men and 25 women) were included. The degree of fibrosis and ballooning in equol-nonproducers was significantly higher than in equol-producers in women. The percentage of nonproducers with NAFLD activity score (NAS) ≥ 5 was significantly higher than that of producers. None of the histological features were significantly different between nonproducers and producers in men. Decision tree analysis identified predictors for NAS ≥ 5 in women. The status of equol production was the strongest predictor, followed by fasting glucose. Since equol can be noninvasively detected in urine, it can be applied as a screening tool for the progression of NASH in women.

Mortality and recurrence rates of hepatocellular carcinoma (HCC) are high. Recent studies show that for patients with HCC beyond up-to-seven criteria, treatment with molecular-targeted agents (MTAs) is recommended because the treatment efficiency of transcatheter arterial chemoembolization (TACE) is poor; further, TACE increases decline in liver function. However, the relationship between TACE and liver function decline in patients with HCC within up-to-seven criteria has not been clarified. Hence, we aimed to investigate this relationship. This retrospective observational study included 189 HCC tumors within up-to-seven criteria in 114 Child-Pugh class A patients. Twenty-four (12.7%) tumors were changed from Child-Pugh class A to B after TACE, and 116 (61.4%) tumors exhibited recurrence within 6 months after TACE. Prothrombin time (PT) and albumin-bilirubin (ALBI) score before TACE were significantly associated with liver dysfunction from Child-Pugh class A to B. The combination of PT and ALBI score before TACE had high predictive ability for liver dysfunction from Child-Pugh class A to B after TACE (specificity = 100%, sensitivity = 91.7%). The combined use of pre-TACE PT and ALBI score has a high predictive ability for liver dysfunction after TACE for Child-Pugh class A patients with HCC within up-to-seven criteria.

Objectives: This study aimed to evaluate and compare the outcomes of palliative endoscopic biliary stenting (EBS) and complete stone removal among elderly patients with choledocholithiasis using propensity score matching., Methods: From April 2012 to October 2017, 161 patients aged 75 years and older with choledocholithiasis underwent endoscopic retrograde cholangiopancreatography at our institution. Among them, 136 (84.5%) had complete stone removal, and 25 (15.5%) underwent palliative EBS without further intervention until symptom occurrence. The median age of the EBS group was significantly higher than that of the complete stone removal group. The proportion of patients with dementia, cerebral infarction, preserved gallbladder with gallstones, and surgically altered anatomy was higher in the EBS group than in the complete stone removal group. Propensity score matching was used to adjust for different factors. In total, 50 matched patients (n = 25 in each group) were analyzed., Results: The median duration of cholangitis-free periods was significantly shorter in the EBS group (596 days) than in the complete stone removal group. About half of patients in the EBS group required retreatment and rehospitalization for cholangitis during the observation period. Cholangitis was mainly caused by stent migration. There was no significant difference in terms of mortality rate and procedure-related adverse events between the two groups. Death was commonly attributed to underlying diseases. However, one patient in the EBS group died due to severe cholangitis., Conclusions: Palliative EBS should be indicated only to patients with choledocholithiasis who have a poor prognosis., (© 2021. The Author(s).)

Abstract: The presence of bridging fibrosis predicts survival of primary biliary cholangitis (PBC). This study aimed to compare serum parameters for the estimation of liver fibrosis and prediction of clinical outcomes in PBC.Out of 392 patients with PBC, 102 who underwent liver biopsy and in whom fibrosis indices, platelet count, hyaluronic acid, type IV collagen 7 second domain, procollagen type III amino-terminal peptide, tissue inhibitor of metalloproteinases 1, Mac-2 binding protein glycosylation isomer, N-terminal type III collagen propeptide levels; fibrosis index based on 4 factors, aspartate aminotransferase-to-platelet ratio index, and enhanced liver fibrosis (ELF) score were determined, were included. The correlation of histological stages based on both Scheuer and Nakanuma classifications with fibrosis indices was investigated. The Nakanuma system comprises grading for liver fibrosis and bile duct loss. Diagnostic performances of 10 fibrosis indices were evaluated to identify patients with poor prognosis. Moreover, correlations of those with PBC clinical manifestation and survival were also investigated.Enhances liver fibrosis (ELF) score had the highest correlation coefficient for liver fibrosis evaluated according to either the Scheuer or Nakanuma classification among 10 serum fibrosis indices. It also had the highest diagnostic performance in estimating Scheuer stage III and Nakanuma fibrosis score 2, both of which represent portal-bridging fibrosis. Patients with an ELF score of ≥10.0 had shorter survival and presented more frequently clinical complications than those with an ELF score of <10.0.ELF score determines the severity of liver fibrosis and predicts the occurrence of complications and survival in patients with PBC., Competing Interests: The authors have no conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Abstract: We aimed to prospectively identify the risk factors of sarcopenia in patients with cirrhosis.Patients (n = 193) included in a discovery cohort (January 2011 and December 2014) were categorized into alcoholic (A1; n = 55) and non-alcoholic cirrhosis (NA; n = 138) groups, and those (n = 235) in a validation cohort (January 2015 to December 2019) were categorized into alcoholic (n = 92), non-alcoholic steatohepatitis-related (n = 27), and hepatitis C virus-related cirrhosis groups (n = 116). Skeletal muscle mass index (SMI) was determined using computed tomography (SMI-CT) and bioelectrical impedance analysis (SMI-BIA). Endotoxin activity (EA) was measured with an EA assay.SMI-CT correlated with grip strength in all the groups but significantly correlated with SMI-BIA of the men in group A1 (R = 0.64, P < .0001) and both sexes in group NA (male: R = 0.44, P = .0001; female: R = 0.35, P = .003). SMI-CT inversely correlated with the EA levels of the men in group A1 (R = -0.67, P < .0001) and myostatin levels in group NA (R = -0.53, P < .0001). Lower extremity SMI had a strong negative correlation with the EA levels of the men in group A1 (R = -0.58, P < .001), whereas upper extremity SMI showed an inverse trend with EA levels (R = -0.28, P = .08). SMI-CT also inversely correlated with the EA levels in groups A2 (R = -0.52, P = .003) and N (R = -0.67, P < .0001) and myostatin levels in group C (R = -0.65, P < .0001). Moreover, SMI-CT correlated with nutritional factors, including cholinesterase (R = 0.50, P = .005), zinc (R = 0.45, P = .01), branched amino acid-to-tyrosine ratio (R = 0.39, P = .02), and triglyceride (R = 0.33, P = .03) in group N.Sarcopenia risk factors differ among cirrhosis etiologies. Alcohol-induced, intestine-mediated peripheral endotoxemia could participate in sarcopenia development in patients with alcoholic cirrhosis., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: This study aimed to compare the diagnostic performance of carbohydrate-deficient transferrin (CDT) and gamma-glutamyltranspeptidase (γ-GTP) to assess the single and combined benefits of these biological markers for the detection of chronic excessive alcohol consumption in patients with alcoholic cirrhosis. Methods: Biological markers were determined in blood samples from patients with alcoholic cirrhosis (drinking group, n = 35; nondrinking group, n = 81). The prediction accuracy of %CDT alone, γ-GTP alone, and their combination for the detection of excessive alcohol consumption was determined in patients with alcoholic cirrhosis. Results: Serum total bilirubin, alanine aminotransferase, aspartate aminotransferase, γ-GTP, and alkaline phosphatase levels and %CDT were significantly higher and serum albumin levels were significantly lower in the drinking group than in the nondrinking group. The combination of %CDT and γ-GTP compared with %CDT or γ-GTP alone showed a higher prediction accuracy. The combination of %CDT and γ-GTP exhibited a higher specificity than γ-GTP alone. However, in terms of sensitivity, no significant difference was found between single or combined markers. Conclusions: The combination of %CDT and γ-GTP is considered a useful biomarker of chronic excessive alcohol consumption in patients with alcoholic cirrhosis.

Background: Methotrexate-associated lymphoproliferative disorder (MTX-LPD) is a rare but critical complication that develops in patients treated with MTX. Although MTX-LPD has been recently reported, the incidence of follicular lymphoma in the intestine is very low., Case Presentation: A 73-year-old woman who had been receiving MTX for over 10 years visited our hospital complaining of postprandial abdominal pain and nausea. Upper and lower digestive tract endoscopies did not show any abnormal findings. A patency capsule was stagnated at the proximal part of the ileum with a mild dilation on the oral side. An oral balloon endoscopy revealed shallow ulcerative lesions in the jejunum. She was diagnosed with MTX-LPD based on histopathological findings. The symptoms did not improve with the discontinuation of MTX, and the patient required partial resection of the small intestine. The test result for Epstein-Barr virus-encoded small RNA was negative. She was diagnosed with follicular lymphoma based on the histology findings of a surgical specimen. Postoperative positron emission tomography-computed tomography and bone marrow aspiration did not show any findings of lymphoma. On follow-up, no recurrence was noted four years after the surgery., Conclusions: Herein, we report the first case of follicular lymphoma that occurred in the small intestine, negative for Epstein-Barr virus-encoded small RNA. If intestinal symptoms occur during MTX administration, it is important to directly observe by endoscopy and perform histological examination.

Recent studies have suggested that an alteration in the gut microbiota and their products, particularly endotoxins derived from Gram-negative bacteria, may play a major role in the pathogenesis of liver diseases. Gut dysbiosis caused by a high-fat diet and alcohol consumption induces increased intestinal permeability, which means higher translocation of bacteria and their products and components, including endotoxins, the so-called "leaky gut". Clinical studies have found that plasma endotoxin levels are elevated in patients with chronic liver diseases, including alcoholic liver disease and nonalcoholic liver disease. A decrease in commensal nonpathogenic bacteria including Ruminococaceae and Lactobacillus and an overgrowth of pathogenic bacteria such as Bacteroidaceae and Enterobacteriaceae are observed in cirrhotic patients. The decreased diversity of the gut microbiota in cirrhotic patients before liver transplantation is also related to a higher incidence of post-transplant infections and cognitive impairment. The exposure to endotoxins activates macrophages via Toll-like receptor 4 (TLR4), leading to a greater production of proinflammatory cytokines and chemokines including tumor necrosis factor-alpha, interleukin (IL)-6, and IL-8, which play key roles in the progression of liver diseases. TLR4 is a major receptor activated by the binding of endotoxins in macrophages, and its downstream signal induces proinflammatory cytokines. The expression of TLR4 is also observed in nonimmune cells in the liver, such as hepatic stellate cells, which play a crucial role in the progression of liver fibrosis that develops into hepatocarcinogenesis, suggesting the importance of the interaction between endotoxemia and TLR4 signaling as a target for preventing liver disease progression. In this review, we summarize the findings for the role of gut-derived endotoxemia underlying the progression of liver pathogenesis.

The progression of nonalcoholic steatohepatitis (NASH) is complicated. The multiple parallel-hits theory is advocated, which includes adipocytokines, insulin resistance, endotoxins, and oxidative stress. Pathways involving the gut-liver axis also mediate the progression of NASH. Angiotensin-II receptor blockers (ARB) suppress hepatic fibrosis via the activation of hepatic stellate cells (HSCs). Rifaximin, a nonabsorbable antibacterial agent, is used for the treatment of hepatic encephalopathy and has been recently reported to improve intestinal permeability. We examined the inhibitory effects on and mechanism of hepatic fibrogenesis by combining ARB and rifaximin administration. Fischer 344 rats were fed a choline-deficient/l-amino acid-defined (CDAA) diet for 8 weeks to generate the NASH model. The therapeutic effect of combining an ARB and rifaximin was evaluated along with hepatic fibrogenesis, the lipopolysaccharide-Toll-like receptor 4 (TLR4) regulatory cascade, and intestinal barrier function. ARBs had a potent inhibitory effect on hepatic fibrogenesis by suppressing HSC activation and hepatic expression of transforming growth factor-β and TLR4. Rifaximin reduced intestinal permeability by rescuing zonula occludens-1 (ZO-1) disruption induced by the CDAA diet and reduced portal endotoxin. Rifaximin directly affect to ZO-1 expression on intestinal epithelial cells. The combination of an ARB and rifaximin showed a stronger inhibitory effect compared to that conferred by a single agent. ARBs improve hepatic fibrosis by inhibiting HSCs, whereas rifaximin improves hepatic fibrosis by improving intestinal permeability through improving intestinal tight junction proteins (ZO-1). Therefore, the combination of ARBs and rifaximin may be a promising therapy for NASH fibrosis.

Despite the use of various pharmacotherapeutic strategies, fibrosis due to nonalcoholic steatohepatitis (NASH) remains an unsatisfied clinical issue. We investigated the effect of sevelamer, a hydrophilic bile acid sequestrant, on hepatic fibrosis in a murine NASH model. Male C57BL/6J mice were fed a choline-deficient, L-amino acid-defined, high-fat (CDHF) diet for 12 weeks with or without orally administered sevelamer hydrochloride (2% per diet weight). Histological and biochemical analyses revealed that sevelamer prevented hepatic steatosis, macrophage infiltration, and pericellular fibrosis in CDHF-fed mice. Sevelamer reduced the portal levels of total bile acid and inhibited both hepatic and intestinal farnesoid X receptor activation. Gut microbiome analysis demonstrated that sevelamer improved a lower α-diversity and prevented decreases in Lactobacillaceae and Clostridiaceae as well as increases in Desulfovibrionaceae and Enterobacteriaceae in the CDHF-fed mice. Additionally, sevelamer bound to lipopolysaccharide (LPS) in the intestinal lumen and promoted its fecal excretion. Consequently, the sevelamer treatment restored the tight intestinal junction proteins and reduced the portal LPS levels, leading to the suppression of hepatic toll-like receptor 4 signaling pathway. Furthermore, sevelamer inhibited the LPS-mediated induction of fibrogenic activity in human hepatic stellate cells in vitro. Collectively, sevelamer inhibited the development of murine steatohepatitis by reducing hepatic LPS overload.

We herein report a 52-year-old man with multiple hypoechoic lesions in the body and tail of the pancreas detected during a screening ultrasound. Computed tomography (CT) showed no lesions other than those in the pancreas and peripheral lymph nodes. Contrast-enhanced CT identified hypovascular tumors in the pancreas. Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) demonstrated partial fibrosis and noncaseating granulomas with Langhans giant cells. To our knowledge, this is the first report of isolated pancreatic sarcoidosis diagnosed by EUS-FNA. Although pancreatic sarcoidosis is very rare, clinicians should be aware of this possibility in patients presenting with multiple hypovascular pancreatic tumors.

It is unclear whether the link between non-alcoholic fatty liver disease (NAFLD) and chronic kidney disease (CKD) is mediated by common risk factors. We aimed to elucidate the association between NAFLD and CKD using propensity score (PS)-matched analysis. We assessed 3725 Japanese individuals, excluding those with hepatitis B or C infection and men and women who consumed >30 and >20 g/day of alcohol, respectively. Of these, we enrolled 1097 Japanese subjects with NAFLD diagnosed by ultrasonography and 1097 PS-matched subjects without NAFLD. The prevalence of CKD was higher in subjects with NAFLD than in those without NAFLD before PS matching, but there was no significant difference between these groups in terms of CKD prevalence after PS matching. There was no difference in the prevalence of CKD between those with and without NAFLD in the subgroup analyses. Logistic regression analysis demonstrated that obesity, hypertension, and hyperuricemia were independent predictors of CKD, but NAFLD was not independently associated with CKD. In subjects with NAFLD, obesity, hypertension, and hyperuricemia were independent predictors of CKD. Thus, the link between NAFLD and CKD may be mediated by common risk factors. We recommend screening for CKD when patients with NAFLD have the aforementioned comorbidities.

We aimed to elucidate the effect of chronic alcohol consumption on fatty liver. We assessed the consumption of alcohol in 2429 Japanese males (mean age: 54.2 ± 9 years); they were classified according to average consumption into non-drinkers (ND), light drinkers (LD), moderate drinkers (MD), and heavy drinkers (HD). The prevalence of fatty liver was the lowest in the MD and highest in the ND group ( p < 0.001), while obesity was not significantly different among the groups ( p = 0.133). Elevated levels of alanine aminotransferase (ALT) were the lowest in the MD group ( p = 0.011) along with resistance to insulin (homeostasis model assessment-insulin resistance (HOMA-IR)), which was highest in the ND group ( p = 0.001). Chronic consumption of alcohol was independently and inversely associated with fatty liver and insulin resistance after adjusting for obesity, hypertension, fasting hyperglycemia, habit of drinking sweet beverages, physical activity, and age (odds ratios are as follows: ND, 1; LD, 0.682; MD, 0.771; HD, 0.840 and ND, 1; LD, 0.724; MD, 0.701; HD, 0.800, respectively). We found that regardless of the type of alcoholic beverage, chronic consumption of alcohol is inversely associated with insulin resistance and fatty liver in Japanese males. This study had limitations, most notably the lack of investigation into diet and nutrition.

Rifaximin is a poorly absorbable antibiotic against hepatic encephalopathy (HE). This observational study aimed to elucidate the effect of rifaximin on intestinal permeability and gut microbiota in patients with decompensated cirrhosis. Thirty patients with decompensated cirrhosis were assessed by ammonia level, neuropsychological testing, endotoxin activity (EA), and serum proinflammatory cytokines at baseline and after four weeks of rifaximin treatment (1200 mg/day). Intestinal permeability was indicated by serum soluble CD163 (sCD163), mannose receptor (sMR), and zonulin levels. To evaluate the gut microbiome, 16S ribosomal RNA gene sequencing was applied. Rifaximin ameliorated hyperammonemia and cognitive dysfunction, although it did not change the serum proinflammatory cytokine levels. It decreased EA levels as well as serum levels of sCD163 and sMR, but not zonulin, and both decreases in sCD163 and sMR showed positive correlations with EA decrease (ΔsCD163: Correlation coefficient (R) = 0.680, p = 0.023; ΔsMR: R = 0.613, p = 0.014, vs. ΔEA). Gut microbial analysis revealed that the richness and complexity of species were unchanged while the abundance of the Streptococcus genus was reduced after treatment with rifaximin. Collectively, rifaximin alleviated HE and endotoxemia with improved intestinal hyperpermeability in patients with decompensated cirrhosis, and this effect is partially involved in a gut microbial change., Competing Interests: Funding: This research received no external funding

Hepatocellular carcinoma (HCC) is the strongest independent predictor of mortality in non-alcoholic steatohepatitis (NASH)-related cirrhosis. The effects and mechanisms of combination of sodium-dependent glucose cotransporter inhibitor and canagliflozin (CA) and dipeptidyl peptidase-4 inhibitor and teneligliptin (TE) on non-diabetic NASH progression were examined. CA and TE suppressed choline-deficient, L-amino acid-defined diet-induced hepatic fibrogenesis and carcinogenesis. CA alone or with TE significantly decreased proinflammatory cytokine expression. CA and TE significantly attenuated hepatic lipid peroxidation. In vitro studies showed that TE alone or with CA inhibited cell proliferation and TGF-β1 and α1 (I)-procollagen mRNA expression in Ac-HSCs. CA+TE inhibited liver fibrogenesis by attenuating hepatic lipid peroxidation and inflammation and by inhibiting Ac-HSC proliferation with concomitant attenuation of hepatic lipid peroxidation. Moreover, CA+TE suppressed in vivo angiogenesis and oxidative DNA damage. CA or CA+TE inhibited HCC cells and human umbilical vein endothelial cell (HUVEC) proliferation. CA+TE suppressed vascular endothelial growth factor expression and promoted increased E-cadherin expression in HUVECs. CA+TE potentially exerts synergistic effects on hepatocarcinogenesis prevention by suppressing HCC cell proliferation and angiogenesis and concomitantly reducing oxidative stress and by inhibiting angiogenesis with attenuation of oxidative stress. CA+TE showed chemopreventive effects on NASH progression compared with single agent in non-diabetic rat model of NASH, concurrent with Ac-HSC and HCC cell proliferation, angiogenesis oxidative stress, and inflammation. Both agents are widely, safely used in clinical practice; combined treatment may represent a potential strategy against NASH.

Background and Aim: Hypothyroidism might play a crucial role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). The association of subclinical hypothyroidism with NAFLD has been inconsistent. The relationship of NAFLD with thyroid function parameters and subclinical hypothyroidism was determined., Methods: This cross-sectional study included 70 patients with subclinical hypothyroidism and 70 controls with euthyroidism matched according to gender, age, and body mass index (BMI). NAFLD was diagnosed via abdominal ultrasonography. The association between NAFLD and subclinical hypothyroidism was analyzed., Results: The prevalence of NAFLD was significantly higher in patients with subclinical hypothyroidism than in those with euthyroidism. Multivariate analysis showed that subclinical hypothyroidism was an independent risk factor of NAFLD adjusted by metabolic-related factors, such as BMI, triglyceride, high-density lipoprotein-cholesterol, hypertension, and diabetes. Thyroid-stimulating hormone (TSH) was an independent risk factor of NAFLD adjusted by the same metabolic-related factors, but free thyroxine (FT4) was not a risk factor. The FIB-4 index, a noninvasive marker of liver fibrosis was significantly higher in patients with subclinical hypothyroidism than in those with euthyroidism. Compared with patients with euthyroidism, the proportion of the FIB-4 index ≥2.67 was significantly higher, and the proportion of the FIB-4 index <1.30 was lower in patients with subclinical hypothyroidism., Conclusions: TSH elevation even within the euthyroid range is an independent risk factor of NAFLD and may influence the progression of liver fibrosis, even with a normal FT4 level., (© 2019 The Authors. JGH Open: An open access journal of gastroenterology and hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Aim: Non-alcoholic steatohepatitis (NASH) has a broad clinicopathological spectrum (inflammation to severe fibrosis). The farnesoid X receptor agonist obeticholic acid (OCA) ameliorates the histological features of NASH; satisfactory antifibrotic effects have not yet been reported. Here, we investigated the combined effects of OCA + a dipeptidyl peptidase-4 inhibitor (sitagliptin) on hepatic fibrogenesis in a rat model of NASH., Methods: Fifty Fischer 344 rats were fed a choline-deficient L-amino-acid-defined (CDAA) diet for 12 weeks. The in vitro and in vivo effects of OCA + sitagliptin were assessed along with hepatic fibrogenesis, lipopolysaccharide-Toll-like receptor 4 (TLR4) regulatory cascade and intestinal barrier function. Direct inhibitory effects of OCA + sitagliptin on activated hepatic stellate cells (Ac-HSCs) were assessed in vitro., Results: Treatment with OCA + sitagliptin potentially inhibited hepatic fibrogenesis along with Ac-HSC proliferation and hepatic transforming growth factor (TGF)-β1, α1(I)-procollagen, and tissue inhibitor of metalloproteinase-1 (TIMP-1) mRNA expression and hydroxyproline levels. Obeticholic acid inhibited hepatic TLR4 expression and increased hepatic matrix metalloproteinase-2 expression. Obeticholic acid decreased intestinal permeability by ameliorating CDAA diet-induced zonula occludens-1 disruption, whereas sitagliptin directly inhibited Ac-HSC proliferation. The in vitro suppressive effects of OCA + sitagliptin on TGF-β1 and α1(I)-procollagen mRNA expression and p38 phosphorylation in Ac-HSCs were almost consistent. Sitagliptin directly inhibited the regulation of Ac-HSC., Conclusions: Treatment with OCA + sitagliptin synergistically affected hepatic fibrogenesis by counteracting endotoxemia induced by intestinal barrier dysfunction and suppressing Ac-HSC proliferation. Thus, OCA + sitagliptin could be a promising therapeutic strategy for NASH., (© 2019 The Japan Society of Hepatology.)

Hyperglycemia and hyperinsulinemia activate the proliferative potential of hepatic stellate cells (HSCs) and promote hepatic fibrosis. Dipeptidyl peptidase-4 (DPP-4) inhibitors, antidiabetic agents, reportedly inhibit the HSC proliferation. Additionally, Takeda G protein-coupled receptor 5 (TGR5) agonists induce the systemic release of glucagon-like peptides from intestinal L cells, which maintains glycemic homeostasis. This study assessed the combined effect of TGR5 agonist and DPP-4 inhibitor on diabetes-based liver fibrosis development. Male diabetic rats received intraperitoneal injection of porcine serum (PS) to induce liver fibrosis, and they were orally administered the following agents: oleanolic acid (OA) as a TGR5 agonist, anagliptin (ANA) as a DPP-4 inhibitor, and a combination of both agents. Treatment with OA or ANA significantly improved glycemic status and attenuated intrahepatic steatosis and lipid peroxidation in diabetic rats. PS-induced liver fibrosis development was also drastically suppressed by treatment with either agent, and the combination of both reciprocally enhanced the antifibrotic effect. Fecal microbiome demonstrated that both agents inhibited the increase in the Firmicutes/Bacteroidetes ratio, an indicator of dysbiosis related to metabolic syndromes. Furthermore, ANA directly inhibited in vitro HSC proliferative and profibrogenic activities. Collectively, TGR5 agonist and DPP-4 inhibitor appears to be a novel strategy against liver fibrosis under diabetic conditions.

Aim: To identify laboratory predictors of histological progression (HP) of primary biliary cholangitis (PBC)., Methods: Sequential biopsies were carried out on 35 (11.4%) of 308 patients with PBC treated with ursodeoxycholic acid (UDCA). Patients were divided into high γ-glutamyl transpeptidase (GGT) (n = 18) and low GGT (n = 17) groups, based on the median value of GGT at baseline. Patients were then categorized as showing HP (progressive group, PG) or lacking HP (non-progressive group, NPG) according to the Scheuer and Nakanuma classifications, with the latter grading liver fibrosis (fibrosis score) and bile duct loss (BDL score)., Results: According to the Scheuer definition, 12 patients had HP and 23 did not. According to the Nakanuma definition, 8 and 27 patients were in the PG and NPG groups, respectively. The fibrosis and BDL scores progressed in 13 and 8 patients, respectively, whereas 22 and 25 patients did not show HP, respectively. Fisher's exact probability test analysis revealed that the rate of HP using the Nakanuma fibrosis score was significantly higher in the high GGT group compared to the low GGT group (P < 0.05). However, no significant correlation was found between the HP of PBC and the biochemical response to UDCA therapy. Both univariate and multivariate logistic regression analyses indicated that the serum GGT level at baseline is an independent risk factor for an increased Nakanuma fibrosis score., Conclusions: The level of serum GGT at baseline is significantly associated with liver fibrosis progression in PBC, and therefore could help to predict the HP of PBC., (© 2019 The Japan Society of Hepatology.)

Rationale: Mucinous cystic neoplasms (MCNs) are pancreatic mucin-producing cystic lesions with a distinctive ovarian-type stroma. The diagnosis is generally easy in typical cases; however, differential diagnosis is difficult in others such as in the case we report herein., Patient Concerns: A 27-year-old woman with sudden onset of epigastric pain was referred to our hospital for suspected acute pancreatitis. Contrast-enhanced computed tomography revealed a 25-mm cystic lesion in the pancreas and a low density area with delayed enhancement at the right upper side of the cystic lesion., Diagnoses: During its clinical course, the cystic lesion underwent various morphological changes. Eventually, it presented typical findings of MCNs, and could be accurately diagnosed., Interventions: Laparoscopic distal pancreatectomy was performed on the patient by preserving the spleen., Outcomes: The patient revealed no symptoms till 1 year after the operation., Lessons: This case of MCN with intriguing short-term morphological changes was associated with recurrent pancreatitis. A combination of imaging modalities is essential for accurate diagnosis of MCNs, and follow-up with serial imaging might be useful for certain unusual lesions.

Objectives: The diagnostic yield of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) cytology widely varies depending on the treatment method used. Liquid-based cytology (LBC) has gained popularity in the gynecological field because of its efficacy in collection of target cells and simplicity in the manipulation of specimens. Since the introduction of EUS-FNA at our institution, we have used LBC for the diagnosis of pancreatic mass lesions. This study aims to investigate the diagnostic efficacy of EUS-FNA with LBC in patients with pancreatic mass lesions during the learning curve for EUS-FNA., Methods: In this study, we retrospectively enrolled 222 patients with pancreatic mass lesions who were diagnosed using EUS-FNA with LBC between 2011 and 2016. The diagnostic yields for EUS-FNA with LBC for pancreatic mass lesions were evaluated., Results: The diagnostic sensitivity, specificity, and accuracy for malignancy were found to be 93.9%, 95.1%, and 94.1%, respectively., Conclusions: This study suggests that EUS-FNA with LBC for specimens provides good diagnostic efficacy in patients with pancreatic mass lesions even during the learning curve for EUS-FNA.

Background: Gastric cancer has a wide spectrum of clinical features, imaging manifestations, and pathology. Punctate calcifications in gastric cancer are infrequent but are usually found in mucinous adenocarcinoma. However, there have only been a few autopsy case reports describing the correlation between the radiology and pathology findings of calcified mucinous adenocarcinoma of the stomach. We present an autopsy case of mucinous gastric adenocarcinoma with iris metastases as the initial symptom., Case Presentation: A 74-year-old Japanese woman presented with blurred vision. Her treating ophthalmologist diagnosed acute iritis with secondary glaucoma. The histopathological and immunohistochemical features of a trabeculectomy specimen favored metastatic carcinoma, most likely of gastrointestinal tract origin. Esophagogastroduodenoscopy revealed multiple irregularly shaped ulcerative lesions, multiple erosions, and thickened folds in the corpus of her stomach. Histologic examination of a gastric tissue specimen obtained by endoscopic biopsy revealed poorly differentiated carcinoma with signet ring cell features. Computed tomography revealed a tumor with multiple punctate calcifications in the thickened gastric wall with diffuse low attenuation and multiple lymph node metastases, including the para-aortic lymph nodes, and peritoneal dissemination. She was diagnosed with stage IV gastric cancer (T4N3M1) and underwent seven cycles of 5-weekly TS-1, a novel oral fluoropyrimidine derivative, plus cisplatin therapy. Serial follow-up computed tomography revealed successive increases in the gastric wall calcifications. Her disease stabilized, but she died of aspiration pneumonia 8 months after the first visit. Autopsy tissue specimens had miliary, punctate calcifications present in abundant extracellular mucin pools in the submucosa, corresponding to the thickened low-attenuating middle layer on computed tomography. The final diagnosis was mucinous gastric adenocarcinoma because mucinous adenocarcinoma is diagnosed when more than half of the tumor area contains extracellular mucin pools., Conclusions: We report the pathology and computed tomography imaging characteristics of a case of calcified mucinous adenocarcinoma of the stomach metastatic to the iris, including findings at autopsy. Metastatic carcinomas in the iris originating in the stomach are exceedingly rare. Multiple punctate calcifications were present in pools of extracellular mucin, a diagnostic clue for mucinous adenocarcinoma. Possible mechanisms underlying scattered punctuate calcifications in gastric mucinous adenocarcinoma warrant further investigation.

Aim: Proton pump inhibitors (PPIs) are frequently prescribed in patients with cirrhosis, but this therapy entails potential complications. We aimed to investigate the influence of PPI use on intestinal permeability in patients with cirrhosis., Methods: We recruited 228 patients with cirrhosis and divided them into four groups. Group (Gp)1 comprised patients receiving a PPI with concurrent neomycin (NEO) (PPI-NEO group, n = 14 [6.1%]), Gp2 and Gp3 comprised those receiving either PPI or NEO (PPI group, n = 91 [39.9%]; and NEO group, n = 11 [4.4%]), and Gp4 comprised those receiving neither of these medications (control group; n = 112 [49.1%]). We assessed the intestinal permeability by measuring endotoxin activity (EA) using a luminol chemiluminescence method., Results: Endotoxin activity levels were significantly higher in patients with Child B cirrhosis than in those with Child A cirrhosis, but we found no significant differences in EA levels between patients with Child C cirrhosis and those with either Child A or B cirrhosis. We observed no significant differences in EA levels among groups 1-4. Patients without antibiotic exposure (n = 203), comprising 91 patients on PPI therapy (Gp2) and 112 no-PPI-therapy controls (Gp4), were subdivided according to Child-Pugh (CP) classification. We found no significant differences in EA levels between Gp2 and Gp4 in either CP class., Conclusion: Our results suggest that PPI usage does not have a significant impact on serum levels of gut-derived endotoxins, which are already elevated because of the increased intestinal permeability in patients with cirrhosis., (© 2018 The Japan Society of Hepatology.)

Depression is a major reason for interferon (IFN) therapy cessation. IFN-free direct-acting antiviral (DAA) therapy for depression is not well-documented. Thus, four different IFN-free regimens were assessed in genotype-1 hepatitis C virus (HCV) patients with depression. Overall, 287 HCV genotype-1 patients who received combination therapies with IFN-free DAAs of daclatasvir/asunaprevir (DCV/ASV) (n=84), sofosbuvir/ledipasvir (SOF/LDV) (n=95), ombitasvir/paritaprevir/ritonavir (OBV/PTV/r) (n=74), and elbasvir/grazoprevir (EBR/GZR) (n=34) were included. Treatment-induced depression as a complication of HCV therapy in IFN-free DAA regimens was assessed. The severity of depression was evaluated using the Beck Depression Inventory-II (BDI-II) questionnaire. It was demonstrated that all four DAA regimens achieved similar high efficacy in Japanese patients with HCV genotype-1 infection. Moreover, in seven patients with depression who received the 24-week DCV/ASV treatment regimen, the BDI-II scores significantly increased at week 4 as compared with pretreatment values; furthermore, they decreased below baseline at week 12 despite the rapid decline of serum HCV levels after the initiation of DCV/ASV therapy. The BDI-II scores gradually decreased during therapy in the remaining 77 DCV/ASV-treated patients without depression. The BDI-II scores showed a significant decrease from baseline to the end of treatment with 12-week regimens, including SOF/LDV and EBR/GZR. The 12-week DAA regimen of SOF/LDV and EBR/GZR can be safely used with high efficacy in patients with genotype-1 HCV infection, including those with depression.

The farnesoid X receptor (FXR) agonist, a bile acid-activated nuclear receptor, has been shown to improve the histologic features of nonalcoholic steatohepatitis (NASH); however, a satisfactory effect on hepatic fibrosis has not been achieved. We aimed to investigate the combined effect of FXR agonist and angiotensin II type 1 receptor blocker on hepatic fibrogenesis in rat models of NASH. For 8 weeks, two rat models of NASH were developed. Otsuka Long-Evans Tokushima Fatty (OLETF) rats were administered intraperitoneal injections of 1 mL/kg pig serum (PS) twice a week, whereas Fischer-344 rats were fed a choline-deficient, L-amino acid-defined diet (CDAA). The in vitro and in vivo effects of an FXR agonist (INT747) and an angiotensin II type 1 receptor blocker (losartan) on hepatic fibrogenesis were evaluated. In PS-administered OLETF rats, INT747 and losartan had potent inhibitory effects on hepatic fibrogenesis with suppression of hepatic stellate cell (HSC) activation and expression of transforming growth factor β1 and toll-like receptor 4. INT747 decreased intestinal permeability by ameliorating zonula occuludens-1 disruption, whereas losartan directly suppressed activated-HSC (Ac-HSC) regulation. The in vitro inhibitory effects of INT747 and losartan on messenger RNA expressions of transforming growth factor β1, toll-like receptor 4, and myeloid differentiation factor 88 and phosphorylation of nuclear factor-κB and mothers against decapentaplegic homolog 3 in Ac-HSC were almost in parallel. Losartan directly inhibited the regulation of Ac-HSC. Likewise, INT747 in combination with losartan was beneficial on hepatic fibrogenesis in rats fed with CDAA diet. The therapeutic effects of these agents were almost comparable between PS-administered OLETF and CDAA-treated rats. Conclusion : INT747 and losartan synergistically suppressed hepatic fibrogenesis by reversing gut barrier dysfunction and inhibiting Ac-HSC proliferation. Combined therapy may represent a promising novel approach for NASH. ( Hepatology Communications 2017;1:928-945).